The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/7/259/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 2, July 21, 1997 259-267

Article

Differential Effects of B Cell Receptor and B Cell Receptor–Fc{gamma}RIIB1 Engagement on Docking of Csk to GTPase-activating Protein (GAP)-associated p62

Milena Vuica*, Stephen Desiderio{ddagger},§, and Jonathan P. Schneck*

From the * Department of Pathology and Medicine, the {ddagger} Department of Molecular Biology and Genetics, and § Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The stimulatory and inhibitory pathways initiated by engagement of stimulatory receptors such as the B cell receptor for antigen (BCR) and inhibitory receptors such as Fc{gamma} receptors of the IIB1 type (Fc{gamma}RIIB1) intersect in ways that are poorly understood at the molecular level. Because the tyrosine kinase Csk is a potential negative regulator of lymphocyte activation, we examined the effects of BCR and Fc{gamma}RIIB1 engagement on the binding of Csk to phosphotyrosine-containing proteins. Stimulation of a B lymphoma cell line, A20, with intact anti-IgG antibody induced a direct, SH2-mediated association between Csk and a 62-kD phosphotyrosine-containing protein that was identified as RasGTPase-activating protein–associated p62 (GAP-A.p62). In contrast, stimulation of A20 cells with anti-IgG F(ab')2 resulted in little increase in the association of Csk with GAP-A.p62. The effect of Fc{gamma}RIIB1 engagement on this association was abolished by blockade of Fc{gamma}RIIB1 with the monoclonal antibody 2.4G2. Furthermore, the increased association between Csk and GAP-A.p62 seen upon stimulation with intact anti-Ig was abrogated in the Fc{gamma}RIIB1-deficient cell line IIA1.6 and recovered when Fc{gamma}RIIB1 expression was restored by transfection. The differential effects of BCR and BCR-Fc{gamma}RIIB1–mediated signaling on the phosphorylation of GAP-A.p62 and its association with Csk suggest that docking of Csk to GAP-A.p62 may function in the negative regulation of antigen receptor–mediated signals in B cells.

Address correspondence to Dr. Milena Vuica, Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, PCTB 707, 725 N. Wolfe St., Baltimore, MD 21205. Phone: 410-955-2235; FAX: 410-955-9124; E-mail: mvuica{at}welchlink.welch.jhu.edu

1Abbreviations used in this paper: BCR, B cell receptor for antigen; Csk, COOH-terminal Src kinase; GAP, GTPase-activating protein; GAP-A.p62, RasGAP-associated p62 protein; GST, glutathione S transferase.

Drs. Desiderio and Schneck are co-senior authors.


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